Dual Role of CpG-Stimulated B Cells in the Regulation of Dendritic Cells: Comment on the Article by Berggren et al

Authors

  • Mohan S. Maddur DVM, PhD,

    1. INSERM Unité 872, Université Pierre et Marie Curie UMR S 872, and Université Paris Descartes UMR S 872, Paris, France
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  • Srini V. Kaveri DVM, PhD,

    1. INSERM Unité 872, Université Pierre et Marie Curie UMR S 872, and Université Paris Descartes UMR S 872, Paris, France
    2. INSERM-ICMR International Associated Laboratory IMPACT, National Institute of Immunohaematology, Mumbai, India
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  • Jagadeesh Bayry DVM, PhD

    1. INSERM Unité 872, Université Pierre et Marie Curie UMR S 872, and Université Paris Descartes UMR S 872, Paris, France
    2. INSERM-ICMR International Associated Laboratory IMPACT, National Institute of Immunohaematology, Mumbai, India
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The function of B lymphocytes is not restricted to antibody production; rather, B lymphocytes exert a profound regulatory role by interacting with other immune cells and, in particular, dendritic cells (DCs) ([1-4]). A recent report by Berggren et al described the regulatory effect of B cells on plasmacytoid DCs (PDCs); the study demonstrated that B lymphocytes enhance interferon-α (IFNα) production by PDCs upon stimulation with RNA-containing immune complexes or microbial CpG-containing DNA via cell–cell contact or soluble factors ([5]).

Both myeloid DCs and PDCs have a key role in the pathogenesis of systemic lupus erythematosus (SLE) ([6-8]). It is now well known that SLE is characterized by aberrant maturation and functioning of myeloid DCs. Unabated induction of myeloid DCs from monocytes has also been described in lupus patients. Since CpG-containing DNA motifs are common in lupus patients ([9]), we explored the role of CpG-containing DNA–stimulated B cells on the differentiation of myeloid DCs, to provide a comprehensive picture of B cell function in the regulation of both myeloid DCs and PDCs. We examined the effect of CpG-containing oligonucleotide 2006–stimulated B cells on the differentiation of monocyte-derived DCs.

We found that CpG-stimulated B cells significantly reduced the expression of DC markers (CD1a, DC-SIGN, CD80, CD40, HLA–DR) on differentiated cells (Figure 1A). Thus, CpG stimulation enabled B cells to inhibit differentiation of DCs. In contrast, coculture with unstimulated B cells did not alter DC differentiation. Further, we found that a high ratio of B cells to DCs (4:1) is not required for CpG-stimulated B cells to exert their regulatory effects, since even at a low ratio (1:1), CpG-stimulated B cells significantly inhibited DC differentiation. In addition, CpG-activated B cells caused higher apoptosis of differentiating DCs (Figure 1B).

Figure 1.

Effect of CpG-stimulated B cells on the differentiation of myeloid dendritic cells (DCs). Peripheral blood CD14+ monocytes (Mo) from healthy donors were cultured for 6 days in the presence of granulocyte–macrophage colony-stimulating factor (1,000 IU/106 cells) and interleukin-4 (500 IU/106 cells) alone (DC alone) or with cytokines and CD19+ B cells (at a ratio of 1:1 or 1:4) either unstimulated (Mo+B) or stimulated with CpG-containing oligonucleotide 2006 (0.25 μM) (Mo+B-CpG). A, Expression of surface markers on differentiated DCs, analyzed by flow cytometry on CD20− cells. Bars show the mean ± SEM of mean fluorescence intensities (MFIs) from 5 independent experiments. B, Percentage of annexin V–positive apoptotic-differentiating DCs from day 1 to day 3 following coculture with B cells (at a ratio of 1:4), as analyzed by flow cytometry on CD20− cells. Values are the mean ± SEM of 3 independent experiments. ∗ = P < 0.05 versus DCs alone; # = P < 0.05, by Student's paired 2-tailed t-test. NS = not significant.

These results, taken together with those of Berggren et al, suggest that CpG-stimulated B cells play a dual role in the regulation of DC subsets: inhibition of differentiation and number of myeloid DCs and enhancement of IFNα by PDCs. Thus, by inhibiting the differentiation of myeloid DCs, CpG-stimulated B cells can also act as inflammation and autoimmune process–limiting factors in lupus.

Acknowledgments

Supported by INSERM, CNRS, Université Pierre et Marie Curie, Université Paris Descartes, and the European Union Seventh Framework Programme (project ALLFUN; grant 260338).

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